Novel process for the preparation of simvastatin

ABSTRACT

A process for manufacturing simvastatin is provided using novel intermediates. Thus, for example, lovastatin is reacted with methoxyethylamine, alpha methylated  2 -methylbutyryl side chain of the amide formed, hydrolyzed and lactonized to produce finally simvastatin of high purity.

FIELD OF THE INVENTION

The present invention is related to a novel process for the preparationof simvastatin using novel intermediates.

BACK GROUND OF THE INVENTION

Simvastatin of formula I is known to be active inhibitors of HMG-CoAreductase. The therapeutic uses of simvastatin and related compoundswere disclosed in U.S. Pat. No. 4,444,784.

Various processes for preparing simvastatin were disclosed in the priorart. Processes described in the prior art for preparation of simvastatincan be summarized as under: 1) according to U.S. Pat. No. 4,444,784,lovastatin is hydrolyzed with lithium hydroxide to give lovastatintriol, lactonized to give a diol lactone, silylated 3-OH group, acylatedand finally desilylated; 2) according to U.S. Pat. No. 4,582,915,lovastatin is hydrolyzed to give lovastatin potassium salt, directlyC-methylated at alpha position of 2-methyl butyryl side chain andlactonized; 3) according to U.S. Pat. No. 4,820,850, lovastatin isreacted with monoalkylamine to produce lovastatin monoalkylamide,hydroxy groups are protected with t-butyidimethylsilyl groups,C-methylated at alpha position of 2-methyl butyryl side chain,deprotected, hydrolyzed the amide linkage and lactonized; 4) accordingto U.S. Pat. No. 5,763,646, lovastatin is reacted with monoalkylamine ormonocycloalkylamine to produce lovastatin monoalkyl or cycloalkylamide,C-methylated at alpha position of 2-methyl butyryl side chain,hydrolyzed the amide linkage and lactonized; 5) according to U.S. Pat.No. 6,331,641 B1, lovastatin is hydrolyzed with a base to givelovastatin triol, lactonized to give a diol lactone, protected thehydroxy groups, acylated, deprotected and lactonized; 6) according toU.S. Pat. No. 6,603,022 B1, lovastatin is reacted with secondary amineto form a lovastatin amide, C-methylated at alpha position of 2-methylbutyryl side chain, hydrolyzed the amide linkage and lactonized; and 7)according to U.S. Pat. No. 5,393,893, hydroxyl groups of lovastatinalkylamide, cycloalkylamide or aralkyl amide are protected with phenylboronic acid, C-methylated at alpha position of 2-methyl butyryl sidechain, deprotected, hydrolyzed the amide linkage and lactonized.

The above processes suffer from one or other of the following defects.Selective silylation of triol intermediates is not satisfactory leadingto the low overall yield and the contamination of the final product withunacylated impurity. Incomplete C-methylation of N-alkyl, cycloalkyl oraralkyl of lovastatinamide, which leads to contamination of simvastatinwith lovastatin, thereby requiring additional purification steps.

The present invention provides a novel process for preparing simvastatinin high purity using novel intermediates. The novel process overcomesthe aforesaid defects and is amicable for commercial scale production.

SUMMARY OF THE INVENTION

The present invention provides a novel process for preparing simvastatinusing novel intermediates. The process for preparation of simvastatin offormula I:

-   -   may be represented by the steps of:    -   a) reacting compound of formula II (lovastatin) or formula III:    -   wherein M is H, metal ion or NH₄,    -   with the compound of formula IV:        HNR₁R₂   IV    -   wherein    -   R₁ is —R₅—X—R₆ wherein        -   R₅ is alkyl, arylalkyl or cycloalkyl,        -   X is O or S and        -   R₆ is alkyl, arylalkyl, cycloalkyl or aryl; and    -   R₂ is independently selected from H, alkyl, cycloalkyl,        arylalkyl and a group as defined for R₁;    -   or R₁ and R₂ may be bonded to form a cyclic ether or cyclic thio        ether;    -   to produce a compound of formula V:    -   wherein R₁ and R2 are as defined above,    -   (b) optionally protecting the two hydroxyl groups of the said        compound of the formula V to produce a compound of the formula        VI:    -   wherein R3 and R4 represents suitable protecting groups,    -   (c) methylating the said compound of formula V or VI to give a        compound of formula VIIa or VIIb:    -   wherein R₁, R₂, R₃ and R₄ are as defined above,    -   (d) hydrolyzing the amide group if the product of the above step        is the said compound of formula VIIa or deprotecting the two        protected hydroxy groups prior to hydrolysis if the product of        the above step is the said compound of formula VIIb, optionally        treating the hydrolyzed product with aqueous ammonia, to produce        a compound of formula VIII:    -   wherein M′ is a metal such as sodium or potassium or NH₄,    -   (e) lactonizing the said compound of formula VIII to produce        simvastatin of formula I.

The intermediates of formula V, VI, VIIa and VIIb are novel.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel process for preparing simvastatinusing novel intermediates. The process for preparation of simvastatin offormula I:

-   -   may be represented by the steps of:    -   a) reacting compound of formula II (lovastatin) or formula III:    -   wherein M is H, metal ion or NH₄,    -   with the compound of formula IV:        HNR₁R₂   IV    -   wherein    -   R₁ is —R₅—X—R₆ wherein        -   R₅ is alkyl, arylalkyl or cycloalkyl,        -   X is O or S and        -   R₆ is alkyl, arylalkyl, cycloalkyl or aryl; and    -   R₂ is independently selected from H, alkyl, cycloalkyl,        arylalkyl and a group as defined for R₁;    -   or R1 and R2 may be bonded to form a cyclic ether or cyclic thio        ether;    -   to produce a compound of formula V:    -   wherein R₁ and R2 are as defined above,    -   b) optionally protecting the two hydroxyl groups of the said        compound of the formula V to produce a compound of the formula        VI:    -   wherein R3 and R4 represents suitable protecting groups,    -   c) methylating the said compound of formula V or VI to give a        compound of formula VIIa or VIIb:    -   wherein R₁, R₂, R₃ and R₄ are as defined above,    -   d) hydrolyzing the amide group if the product of the above step        is the said compound of formula VIIa or deprotecting the two        protected hydroxy groups prior to hydrolysis if the product of        the above step is the said compound of formula VIIb, optionally        treating the hydrolyzed product with aqueous ammonia, to produce        a compound of formula VIII:    -   wherein M′ is a metal such as sodium or potassium or NH₄,    -   e) lactonizing the said compound of formula VIII to produce        simvastatin of formula I.

The suitable protecting groups are preferably selected from silylprotecting groups such as t-butyidimethylsilyl or trimethylsilyl groups.

Except otherwise stated the term alkyl refers to C1 to C10 straight orbranched alkyl group, which is optionally substituted by such groups asalkoxy, thioalkoxy, aryloxy, arylthio.

The term aryl refers to phenyl, substituted phenyl, heteroaryl andsubstituted heteroaryl.

The term cycloalkyl refers to C3-C6-cycloalkyl.

The intermediates of formulae V, VI, VIIa and VIIb used in the processfor preparing simvastatin are novel.

Lovastatin of formula II or a compound of formula III is reacted with anamine of formula IV to produce amide of formula V. The preferred groupsof R₁ are methoxyethyl-, ethoxyethyl- and methoxymethyl-, more preferredbeing methoxyethyl and ethoxyethyl. The preferred groups of R₂ are H,methoxyethyl-, ethoxyethyl and methoxymethyl-, more preferred being H,methoxyethyl and ethoxyethyl. R₁ and R₂ together forming morpholinyl-with nitrogen of the formula IV is also preferable. The reaction iscarried out in a solvent such as tetrahydrofuran.

The amide formed is C-methylated at alpha position of 2-methyl butyrylside chain of the said amide to produce a compound of formula VIIa. Theamide of formula V is reacted with an alkali metal amide, wherein alkalimetal is lithium, sodium or potassium, preferably lithium. The reactionis preferably carried out by combining a ethereal or hydrocarbonsolution of the alkali metal amide to a ethereal solution of thecompound of the formula V and stirring the contents for about 1-3 hours,the whole reaction being carried out at a temperature of below −30° C.under anhydrous conditions. To complete the C-methylation, methylhalide, preferably methyl chloride, methyl bromide or methyl iodide,most preferably methyl iodide, is added to the above reaction massslowly for about 45 minutes to 2 hours and contents are stirred at atemperature of below −20° C. for about 10-60 minutes. The reactionmixture is quenched with an excess of water and washed with aqueous HCl.The organic layer is concentrated to give the methylated compound.

The alkali metal amide used in the above process is prepared bycombining a hydrocarbon solution or ethereal solution of a n-butylalkali metal with a dried solution of diethylamine dimethylamine,diisopropyl amine or pyrrolidine. Lithium pyrrolidide in tetrahydrofuranis the preferred the alkali metal amide solution.

The methylated compound formed as above is hydrolyzed with a metalhydroxide such as NaOH or KOH to produce a compound of formula VIIIwherein M is metal, which is preferably isolated as the compound offormula VIII wherein M′ is NH₄. The hydrolysis is preferably carried outin the medium containing an alcohol such as methanol and/or water andthe contents are maintained usually at a temperature above 50° C. forabout 2-10 hours, preferably 5-8 hours and then the solvent is distilledoff under vacuum. Water is added and pH is adjusted to below 7 with anacid such as hydrochloric acid and the product is extracted into anorganic solvent such as ethylacetate. The product is isolated as theammonium salt by adding aq. ammonia solution.

The salt of formula VIII, preferably ammonium salt, formed above issuspended in a hydrocarbon solvent such as toluene and heated to about90° C.-110° C. for 2-15 hours under a purge of nitrogen. The contentsare cooled to 20° C.-30° C. and filtered and filtrate is concentratedunder vacuum. A hydrocarbon solvent such as cyclohexane is added,refluxed for 10 to 60 minutes, then cooled to 5° C.-25° C., stirred for1-12 hours, preferably for 2-5 hours. The lactone is filtered, washedwith a hydrocarbon solvent such as cyclohexane and then dried undervacuum.

In an alternative method for the preparation of simvastatin of formulaI, two hydroxy groups of the amide of formula V produced as describedabove is protected with a suitable protecting groups to produce aprotected amide of formula VI, C-methylated at 2-methylbutyryl sidechain of the said protected amide to produce a compound of formula VIIb,deprotected, hydrolyzed and lactonized to produce simvastatin of formulaI.

Thus, the hydroxyl groups may be protected with silyl protecting groupssuch as t-butyldimethyl silylchloride, trimethylsilylchloride to obtaina compound of formula VI. C-methylation can be carried out essentiallyin the same manner as described above for unprotected amide forproducing a compound of formula VIIb. Protecting groups are then removedby using, for example, HF or HCl and the unprotected compound thusformed is hydrolyzed and lactonized in the same manner as described asabove for the compound of formula VIIa to produce simvastatin of formulaI.

The invention will now be further described by the following examples,which are illustrative rather than limiting.

EXAMPLE 1

Step 1:

Lovastatin (50 gm) is mixed with tetrahydrofuran (100 ml) and methoxyethylamine (140 ml) to obtain a clear solution, the solution is heatedto 50° C. and stirred for 4 hours at the same temperature. Then thesolvent is distilled off at reduced pressure not allowing thetemperature to raise above 50° C., tetrahydrofuran (200 ml) is added tothe residue thus obtained, stirred for 30 minutes and distilled off thesolvent to give 58 gm ofN-methoxyethyl-7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[[2(S)-methylbutanoyl]oxy]-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanamideas residue (HPLC Purity 97.3%).

Step 2:

Tetrahydrofuran (520 ml) and pyrrolidine (90 ml) are mixed and themixture is cooled to −40° C. n-Butyl lithium in hexane (1.6M, 510 ml) isadded under nitrogen atmosphere for 2 hours at −40° C. to −50° C. Thecontents are stirred for 30 minutes at −35° C. to −40° C. The residueobtained in step 1 is dissolved in tetrahydrofuran (200 ml) and added tothe alkali metal amide solution prepared above for 20 minutes at −40° C.to −45° C. The reaction mass is stirred for 1 hour at −40° C. to −45° C.The solution is warmed to −25° C. to −30° C., methyl iodide (29.7 ml) isadded for 1 hour at −25° C. to −30° C. and stirred for 30 minutes at−25° C. to −30° C. Saturated ammonium chloride (55 ml) is added to thereaction mass for 10 minutes at −25° C. to −30° C., the solution is thenallowed to raise the temperature to 25° C., water (250 ml) is added at25° C. and stirred for 10 minutes. Then the layers are separated and theorganic layer is washed with 100 ml of 2N hydrochloric acid. The organiclayer is again washed with water (300 ml), dried on sodium sulfate andconcentrated to 150 ml at reduced pressure not allowing the temperatureto raise above 50° C. to giveN-methoxyethyl-7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[[2,2-dimethyl-butanoyl]oxy]-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanamide.

Step 3:

To the concentrate obtained in step 2 is added methanol (840 ml), water(550 ml) and sodium hydroxide (45 gm) at 25° C. The contents are heatedto 75° C. and maintained for 7 hours at about 75° C. Then the solvent isdistilled off at reduced pressure, cooled to 20° C. and water (400 ml)is added. Then the pH of the reaction mass is adjusted to 5 with 2Nhydrochloric acid at 25° C., ethyl acetate (400 ml) is added and the pHis again adjusted to 3.5 with 2N hydrochloric acid solution. The layersare separated and the aqueous layer is washed with ethyl acetate (200ml). The combined organic layer is dried on sodium sulfate. Ammoniasolution, prepared by mixing aqueous ammonia (20 ml) and methanol (20ml), is added to the reaction mass for 15 minutes at about 25° C.,stirred for 1 hour at 25° C. and again for 1 hour at 0° C.-5° C. Thenthe separated solid is filtered and washed with chilled ethyl acetate(50 ml) to give 28 gm of simvastatin ammonium salt (HPLC Purity 97.5%).

Step 4:

The ammonium salt of step 3 (15 gm) is suspended in toluene (500 ml) andheated at 100° C. under a constant sweep of nitrogen for 5 hours. Thesolution is cooled to 25° C., activated charcoal (1 gm) is added stirredfor 30 minutes and then filtered through celite-bed. The filtrate isconcentrated under reduced pressure to a volume of 70 ml. Cyclohexane(200 ml) is added, refluxed for 20 minutes, cooled to 10° C. and stirredfor 3 hours at 10° C. The precipitated solid is filtered and washed withcold cyclohexane (100 ml) and dried to obtain simvastatin as whitecrystalline product. The product is re-crystallized from absoluteethanol to obtain 13 gm of simvastatin (HPLC Purity 99.7%).

EXAMPLE 2

ToN-Methoxyethyl-7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[[2(S)-methylbutanoyl]oxy]-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanamide obtained by repeating thestep 1 of example 1 is added dimethylformamide (175 ml) and the mixtureis stirred for 1 hour. Imidazole (18 gm) and thentert-butyidimethylsilyl chloride (43 gm) are added. The mixture isstirred for 10 hours at 60° C. The contents are cooled to 10° C.,methanol (10 ml) is added and stirred for 30 minutes at 10° C.Cyclohexane (500 ml) and water (575 ml) are added and product isextracted into cyclohexane layer. The layer is concentrated. The silylprotected lovastatinamide concentrate thus obtained is treated in theessentially same manner as described in step 2 to obtainN-methoxyethyl-7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[[2,2-dimethyl-butanoyl]oxy]-1(S)-naphthyl]-3(R),5(R)-bis(t-butyldimethylsilyloxy)heptanamide. Themethylated product obtained is dissolved in acetonitrile (250 ml),hydrofluoric acid (70 ml, 50% aqueous solution) is added. The mixture isstirred for 2 hours at 25° C., then cooled to 0° C. Aqueous sodiumhydroxide (4N) is slowly added until the pH is raised to 7. The layersare separated, the organic layer is washed with water (250 ml) andconcentrating at reduced pressure to obtainN-methoxyethyl-7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[[2,2-dimethyl-butanoyl]oxy]-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptan amide. The concentrate istreated in the essentially same manner as described in step 3 and thenin step 4 to obtain simvastatin (HPLC Purity 99.6%).

1. A process for the preparation of simvastatin of formula I: whichcomprises the steps of: a) reacting compound of formula II (lovastatin)or formula III:

wherein M is H, metal ion or NH₄, with the compound of formula IV:HNR₁R₂   IV wherein R₁ is —R₅—X—R₆ wherein R₅ is alkyl, arylalkyl orcycloalkyl, X is O or S and R₆ is alkyl, arylalkyl, cycloalkyl or aryl;and R₂ is independently selected from H, alkyl, cycloalkyl, arylalkyland a group as defined for R₁; or R1 and R2 may be bonded to form acyclic ether or cyclic thio ether; to produce a compound of formula V:

wherein R₁ and R2 are as defined above, (b) optionally protecting thetwo hydroxyl groups of the compound of the formula V to produce acompound of the formula VI:

wherein R3 and R4 represents suitable protecting groups, (c) methylatingsaid compound of formula V or VI to give a compound of formula VIIa orVIIb:

wherein R₁, R₂, R₃ and R₄ are as defined above, (d) hydrolyzing theamide group if the product of the above step is said compound of formulaVIIa or deprotecting the two protected hydroxy groups prior tohydrolysis if the product of the above step is said compound of formulaVIIb, optionally treating the hydrolyzed product with aqueous ammonia,to produce a compound of formula VIII:

wherein M′ is a metal such as sodium or potassium or NH₄, and (e)lactonizing said compound of the formula VIII to produce simvastatin offormula I.
 2. A process according to claim 1, wherein the hydroxy groupsare not protected before methylation.
 3. A process according to claim 12, wherein R₁ is selected from methoxyethyl, ethoxyethyl andmethoxymethyl, and R₂ is selected from H, methoxyethyl, ethoxyethyl andmethoxymethyl. 4-28. (canceled)
 29. A process according to claim 2,wherein R₁ is selected from methoxyethyl, ethoxyethyl and methoxymethyl,and R₂ is selected from H, methoxyethyl, ethoxyethyl and methoxymethyl.30. A process according to claim 3, wherein R₁ is selected frommethoxyethyl, ethoxyethyl and methoxymethyl, and R₂ is H.
 31. A processaccording to claim 29, wherein R₁ is selected from methoxyethyl,ethoxyethyl and methoxymethyl, and R₂ is H.
 32. A process according toclaim 1, wherein R₁ is methoxyethyl and R₂ is H.
 33. A process accordingto claim 2, wherein R₁ is methoxyethyl and R₂ is H.
 34. A processaccording to claim 3, wherein R₁ is methoxyethyl and R₂ is H.
 35. Aprocess according to claim 29, wherein R₁ is methoxyethyl and R₂ is H.36. A process according to claim 30, wherein R₁ is methoxyethyl and R₂is H.
 37. A process according to claim 31, wherein R₁ is methoxyethyland R₂ is H.
 38. A process according to claim 1, wherein methylation iscarried out using an alkali metal amide and a methyl halide.
 39. Aprocess according to claim 38, wherein the alkali metal is lithium,sodium or potassium; and the methyl halide is methyl iodide, methylchloride or methyl bromide.
 40. A process according to claim 38, whereinthe alkali metal amide is lithium pyrrolidide and the methylhalide ismethyl iodide.
 41. A process according to claim 39, wherein the alkalimetal amide is lithium pyrrolidide and the methylhalide is methyliodide.
 42. A process according to claim 1, wherein the startingcompound is lovastatin of the formula II.
 43. A process according toclaim 1, wherein R₃ and R₄ represent silyl protecting groups.
 44. Aprocess according to claim 43, wherein the silyl protecting groups areselected from t-butyldimethylsilyl and trimethylsilyl groups.
 45. Aprocess according to claim 1, wherein: i) lovastatin is treated withmethoxyethyl amine in an organic solvent to produce the compound of theformula V wherein R₁ is methoxyethyl- and R₂ is H, ii) methylating theproduct obtained in the previous step with lithium pyrrolidide intetrahydrofuran and methyl iodide to produce the compound of the formulaVIIa wherein R₁ is methoxyethyl- and R₂ is H, iii) hydrolyzing theproduct obtained in the previous step with a strong base to obtain thecompound of the formula VIII, iv) adding aqueous ammonia to the productobtained in the previous step to produce simvastatin ammonium salt, andv) lactonizing the product obtained in the previous step to producesimvastatin.


46. A compound of the formula V: wherein R₁ is —R₅—X—R₆ wherein R₅ isalkyl, arylalkyl or cycloalkyl, X is O or S and P₆ is alkyl, arylalkyl,cycloalkyl or aryl; and R₂ is independently selected from H, alkyl,cycloalkyl, arylalkyl and a group as defined for R₁; Or R₁ and R₂ may bebonded to form a cyclic ether or cyclic thio ether.
 47. The compound ofthe claim 46, wherein R₁ is selected from methoxyethyl, ethoxyethyl andmethoxymethyl, and R₂ is selected from H, methoxyethyl, ethoxyethyl andmethoxymethyl.
 48. The compound of claim 47, wherein R₁ is selected frommethoxyethyl, ethoxyethyl and methoxymethyl, and R₂ is H.
 49. Thecompound of claim 48, wherein R₁ is methoxyethyl and R₂ is H.
 50. Acompound of the formula VI:

wherein R₁ and R₂ are as defined in formula V of claim 46; and R₃ and R₄represent suitable protecting groups.
 51. The compound of claim 50,wherein R₁ is selected from methoxyethyl, ethoxyethyl and methoxymethyl,R₂ is selected from H, methoxyethyl, ethoxyethyl and methoxymethyl andR₃ and R₄ are selected from silyl protecting groups such ast-butyldimethylsilyl and trimethylsilyl groups.
 52. The compound ofclaim 50, wherein R₁ is selected from methoxyethyl, ethoxyethyl andmethoxymethyl, and R₂ is H.
 53. The compound of claim 51, wherein R₁ isselected from methoxyethyl, ethoxyethyl and methoxymethyl, and R₂ is H.54. The compound of claim 52, wherein R₁ is methoxyethyl and R₂ is H.55. The compound of claim 53, wherein R₁ is methoxyethyl and R₂ is H.56. The compound of the formula VIIa:

wherein R₁ and R₂ are as defined in the formula V of claim
 46. 57. Thecompound of the claim 56, wherein R₁ is selected from methoxyethyl,ethoxyethyl and methoxymethyl, and R₂ is selected from H, methoxyethyl,ethoxyethyl and methoxymethyl.
 58. The compound of claim 57, wherein R₁is selected from methoxyethyl, ethoxyethyl and methoxymethyl, and R₂ isH.
 59. The compound of claim 58, wherein R₁ is methoxyethyl and R₂ is H.60. A compound of the formula VIIb:

wherein R1, R2, R3 and R4 are as defined in formula VI of claim
 50. 61.The compound of claim 60, wherein R₁ is selected from methoxyethyl,ethoxyethyl and methoxymethyl, R₂ is selected from H, methoxyethyl,ethoxyethyl and methoxymethyl and R₃ and R₄ are selected from silylprotecting groups such as t-butyldimethylsilyl and trimethylsilylgroups.
 62. The compound of claim 60, wherein R₁ is selected frommethoxyethyl, ethoxyethyl and methoxymethyl, and R₂ is H.
 63. Thecompound of claim 61, wherein R₁ is selected from methoxyethyl,ethoxyethyl and methoxymethyl, and R₂ is H.
 64. The compound of claim62, wherein R₁ is methoxyethyl and R₂ is H.
 65. The compound of claim63, wherein R₁ is methoxyethyl and R₂ is H.